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Now Trending: CRISPR

Nearly everyone has heard references to the “genetic code,” a metaphor for the series of nucleotide bases that makes each of us unique. Many diseases, such as cystic fibrosis and sickle-cell anemia, are caused by point mutations, single digit errors in a series of roughly three billion. Although we have made great progress in understanding these diseases, as of yet there exists no cure.

But what if it were as easy for scientists to edit a patient’s genome as it is for programmers to edit computer code? Thanks to technology developed over the past three years, this may soon be possible.

Enter CRISPR. This new, powerful technology has been in the media a lot recently for its potential to cure everything from hemophilia to sickle-cell to cystic fibrosis. It is being tested for its potential to prevent the spread of HIV and other infectious diseases and to counteract the molecular pathways involved in aging. CRISPR has been lauded as a way to improve agriculture and even bring woolly mammoths back from the dead. What is this new technology, which promises so much for the future of humanity?

A faster and easier method of editing the human genome

CRISPR is shaking up gene therapy by providing a faster and easier method of editing the human genome. For as little as $30 and with minimal specialized training, scientists can remove or insert sequences of bases, potentially ridding a patient of a pre-existing genetic condition. The powerful and highly democratic nature of this technology is a huge leap forward for biomedical research, and has understandably generated a great deal of excitement. CRISPR’s potential is so wide-ranging, in fact, that many leading biologists are calling for researchers to slow down in their use of this software until its implications are fully understood.

The acronym CRISPR stands for “Clustered, Regularly-Interspaced Short Palindromic Repeats” and describes segments originally discovered in bacterial DNA in 1987. These repeats allow bacteria to defend themselves against viruses. They are separated by non-repeating spacers, which are copies of segments of DNA from viruses that a bacterium or its ancestors has encountered before. When the bacterium comes in contact with a recognized virus, the part of its DNA corresponding to that virus is converted to RNA, which, along with a protein called Cas9 (CRISPR-associated protein 9) and another strand of RNA, forms a complex that cuts the viral DNA, disabling it. Three years ago, scientists realized that they could utilize this defense mechanism by using synthetic RNA to cut a desired DNA sequence. The cut portion can either be removed and disabled or replaced with a newly inserted sequence.

This has huge implications for gene therapy, which deals with diseases caused by errors in the genetic code. CRISPR is replacing slower and more expensive gene therapy techniques, such as zinc fingers and TALENs, which are currently undergoing clinical trials in the US. If enough cells can be edited using one of these techniques, the patient will be cured. CRISPR sequences can be injected directly into tissues, or tissues can be removed, edited, and then replaced in the body, as with the blood-forming stem cells related to sickle-cell disease. The CRISPR platform was first tested on an adult animal to correct tyrosinemia in mice last year, and clinical trials for humans are expected to begin in the next one to two years. 2014 also saw a steep rise in NIH funding for CRISPR studies, an indication of advances to come.

The next breakthrough

There are several start-ups feverishly raising money to fund the next big CRISPR-related breakthrough. Caribou Biosciences, founded by Jennifer Doudna in Berkeley, CA, in 2011, has raised $11 million so far. Last year, Doudna co-founded Intellia Therapeutics, which has raised $15 million to “discover, develop, and commercialize human gene and cell therapies,” according to their website. Doudna is one of the pioneers of CRISPR technology and has granted Intellia exclusive license to use the platform she developed with French microbiologist Emmanuelle Charpentier. In 2014, Doudna and Charpentier each received a $3 million Breakthrough Prize, an award funded by internet entrepreneurs such as Mark Zuckerberg and Yuri Milner. Charpentier founded her own Swiss-based startup, CRISPR Therapeutics, and has raised $89 million towards related medical research.

In 2013, Harvard geneticist George Church and Dr. Feng Zhang of the Broad Institute and MIT founded Editas Medicine. They have since raised $43 million for therapeutics research. Dr. Zhang and Dr. Doudna are currently embroiled in a patent scuffle – although Dr. Doudna and Dr. Charpentier first published on the CRISPR-Cas9 DNA-cutting technique in 2012, Dr. Zhang claims to have taken innovative steps to apply the technique to complex cells. Dr. Zhang’s institutions have been granted all patents thus far, although the dispute rages on. While the conflict has mitigated some of the fervor surrounding the industry, investors do not seem deterred: as Jim Flynn of Deerfield Capital Management told Forbes, “Your worst case scenario if you’re first to the market with something that is going to create a survival benefit in a population is maybe you have to pay a royalty, maybe there is a cross-license.” For now, Editas appears to be the one to watch.

At present, most research is focusing on disorders caused by point mutations, such as sickle-cell anemia. In the future, CRISPR will most likely be used to tackle a wide array of genetic diseases, such as heart disease, diabetes, and certain neurological conditions. The platform can be used to further the understanding of more complicated conditions by allowing researchers to quickly develop animal models with multiple mutations, a process that would previously have taken years. Dr. Zhang, who studies the genetic causes behind mental disorders such as schizophrenia and autism, has cut this time down to three weeks.

CRISPR also offers encouraging news for carriers of Huntington’s disease, a devastating genetic illness characterized by the buildup of a poisonous protein in the brain. Before CRISPR, scientists could only add in a healthy copy of the gene in question, which had no effect on the amount of neurotoxin produced by harmful genes. Now scientists are able to delete the gene, and hopefully slow or even stop progression of the illness. Although it will be years before this potential could be realized, it does offer some uplifting news for the future.

The dangers

Because this is the real world, however, technology of great promise comes with a caveat. Such a powerful tool made available so cheaply to so many people will necessitate strict parameters surrounding when and how it may be used. The technology is still in the exploration stage, and is not yet one hundred percent accurate. CRISPR has been known to create edits in places other than where researchers intended, and those errors could give birth to new diseases. While the frequency of such errors varies greatly among cell types, even a low error frequency could be dangerous if the cell is cancer-causing. Changes made to genomes of reproductive cells are heritable, which means they will be passed on to future generations. If CRISPR is used on plants or animals in the wild, this could mean the irreversible disruption of ecosystems. It is impossible to anticipate every consequence of this interference due to the complexity of the environment. At the forefront of many people’s minds is the question of what happens when we turn CRISPR on ourselves – not on present, but future, humans. Depending on who you are, the idea of “designer babies” is either fascinating or repugnant. Some of the world’s top biologists met in Napa, CA, this January to discuss this issue, concluding in Science that “at present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing.”

The Sun Yat-sen findings were rejected from Science and Nature—in part for ethical violations—and were later published in Protein & Cell. Multiple problems sprang up in the study, including erroneous cutting. As Dr. Doudna told Carl Zimmer, “Although it has attracted a lot of attention, the [Chinese] study simply underscores the point that the technology is not ready for clinical application in the human germline. And that application of the technology needs to be on hold pending a broader societal discussion of the scientific and ethical issues surrounding such use.”

It is essential that the platform’s precision increase with its efficiency and accessibility. Time will tell if the excitement generated by CRISPR’s promise has been well placed. Many expect nothing short of a revolution.